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Losartan was renoprotective in diabetic nephropathy independent of its effect on blood pressure

Christian G. Rabbat, MD
[+] Article, Author, and Disclosure Information

*See Glossary.

Source of funding: Merck and Company.

For correspondence: Dr. B.M. Brenner, Brigham and Women’s Hospital, Boston, MA, USA. E-mail bbrenner@partners.org.

Ann Intern Med. 2002;136(3):84. doi:10.7326/ACPJC-2002-136-3-084
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Question: In patients with type 2 diabetes mellitus and nephropathy, what is the renoprotective effect of the angiotensin-II–receptor antagonist (ARA) losartan?

Design: Randomized (allocation concealed*), blinded (clinicians, patients, outcome assessors, and statisticians),* placebo-controlled trial with mean follow-up of 3.4 years (the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL] Study).

Setting: 250 centers worldwide.

Patients: 1513 patients between 31 and 70 years of age (mean age 60 y, 63% men) who had type 2 diabetes and nephropathy defined as a urinary albumin-to-creatinine ratio ≥ 300 mg/g and a serum creatinine level between 115 and 265 µmol/L (≥ 133 µmol/L for men weighing > 60 kg). Exclusion criteria included type 1 diabetes and nondiabetic renal disease. Follow-up was 99.8%.

Intervention: After stratification by baseline level of proteinuria, patients were allocated to receive losartan, 50 to 100 mg/d (n = 751), or placebo (n = 762). Conventional antihypertensive therapy (excluding angiotensin-I–converting enzyme inhibitors and ARAs) was adjusted to target a systolic and diastolic blood pressure < 140 and < 90 mm Hg, respectively.

Main outcome measures: The primary outcome was the composite of a doubling of the baseline serum creatinine level, end-stage renal disease (ESRD), or death. The secondary outcome was the composite of cardiovascular morbidity or mortality.

Main results: Analysis was by intention to treat. Losartan reduced the risk for the primary composite outcome (unadjusted P = 0.02; P = 0.03 after adjustment for blood pressure), doubling of the baseline serum creatinine level (unadjusted P = 0.006), and ESRD (unadjusted P = 0.002) more than did placebo (Table). However, losartan and placebo did not differ for incidence of death (unadjusted P = 0.88) (Table) or the secondary composite outcome of cardiovascular morbidity or mortality (P = 0.26).

Conclusions: Losartan was renoprotective in patients with type 2 diabetes mellitus and nephropathy. This effect was beyond that attributable to blood pressure control.

Losartan vs placebo for type 2 diabetes and nephropathy at mean 3.4 years†

OutcomesLosartanPlaceboRRR (95% CI)‡
Composite outcome§44%47%16% (2 to 28)
Doubling of serum creatinine level22%26%25% (8 to 39)
End-stage renal disease20%26%28% (11 to 42)

†Abbreviations defined in Glossary.

‡Based on Cox regression model.

§Composite outcome = doubling of baseline serum creatinine level, end-stage renal disease, or death.





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